Coronavirus disease 2019-associated thrombotic microangiopathy treated with plasma exchange and antihypertensive therapy in a patient with HIV: A case report with literature review

Rationale: Coronavirus disease 2019 (COVID-19) is an infectious disease that often causes complications in multiple organs and thrombosis due to abnormal blood coagulation. This case report aimed to describe the clinical course of COVID-19-associated thrombotic microangiopathy (TMA) and reviewed the comprehensive information on TMA, thrombotic thrombocytopenic purpura (TTP), and atypical hemolytic uremic syndrome associated with COVID-19 in the past literature. Patient concerns: A 46-year-old Japanese man was diagnosed with human immunodeficiency virus infection 10 years ago and treated with antiretroviral therapy. The patient presented with fever, malaise, hematuria, and bilateral upper abdominal discomfort for the past 4 days. Diagnoses: COVID-19-associated TMA was diagnosed based on a positive polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 and laboratory findings such as thrombocytopenia, acute kidney injury, and hemolytic anemia. Malignant hypertension and human immunodeficiency virus infection were also considered as differential diagnoses of TMA. Interventions: Considering the possibility of TTP, plasma exchange was performed, and glucocorticoids were administered. Hemodialysis was performed for acute kidney injury. Antihypertensive drugs were administered to control the high blood pressure. Outcomes: Platelet count and renal function improved, and hemodialysis was no longer required. The patient was in good general condition and was discharged from the hospital. Lessons: COVID-19-associated TMA should be considered as a differential diagnosis during the COVID-19 epidemic. Excessive inflammation and severe COVID-19 are not essential for TMA development. Early intervention using conventional TMA treatments, such as plasma exchange and corticosteroids, might be important in improving prognosis while differentiating between TTP and atypical hemolytic uremic syndrome. Antihypertensive therapy may be helpful in the treatment of COVID-19-associated TMA.


Introduction
Coronavirus disease 2019 (COVID- 19) is an acute infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most patients present with mild upper respiratory tract symptoms that resolve spontaneously; however, some are complicated by pneumonia. [1] Some of them further develop acute respiratory distress syndrome, which is a serious condition with acute respiratory failure. [1,2] The pathogenesis of COVID-19 is associated with excessive inflammation (cytokine storm) and blood coagulation abnormalities in and outside the lungs, in addition to direct cellular damage caused by the virus. [3][4][5][6] Medicine Therapies include antivirals, immunomodulatory agents, and anticoagulants, as required. [7][8][9] Systemic complications other than those of the lungs are common. Two large observational studies in the United States reported acute kidney injury (AKI) in 32% to 37% of patients hospitalized with COVID-19. [10,11] AKI is associated with the requirement for mechanical ventilation and longer duration of hospitalization. [10][11][12][13] Acute tubular necrosis was the predominant kidney pathologic finding in several studies. [14][15][16][17] A hypercoagulable state, resulting in arterial and venous thromboses, is common in patients with COVID-19. [18] Conversely, thrombotic microangiopathy (TMA), atypical hemolytic-uremic syndrome (aHUS), and thrombotic thrombocytopenic purpura (TTP) are uncommon complications in patients who develop AKI. [14,15] The pathogenesis of diseases associated with COVID-19 is not well understood, and no optimal treatment has been established. We encountered a case of TMA in a patient with human immunodeficiency virus (HIV) infection that was well-controlled by antiretroviral therapy (ART) based on the findings of AKI, thrombocytopenia, and hemolytic anemia. The patient presented with fever, but no upper respiratory tract symptoms. A positive SARS-CoV-2 PCR test result led to a diagnosis of COVID-19. At the time of admission, he had extreme hypertension with organ damage, particularly AKI, which required hemodialysis. Multidisciplinary treatment with glucocorticoids, plasma exchange (PE), and antihypertensive drugs was initiated; hemodialysis was eventually discontinued, and the patient was discharged from the hospital. We report the patient's clinical course and possible pathophysiology and review the literature on TMA, aHUS, and TTP as complications of COVID-19. Informed consent was obtained, and the head of the medical team and the institutional review board have responsibility for the anonymization of the patient.

Case
A 46-year-old Japanese man was diagnosed with an HIV infection 10 years ago. The HIV infection was controlled with fosamprenavir, ritonavir, tenofovir, alafenamide (TAF), and emtricitabine (FTC). Five days before admission, ART was switched to darunavir, cobicistat, TAF, and FTC. Although he had hypertension and was prescribed candesartan, he did not take the drug regularly. Four days prior to admission, he presented to the clinic with fever, fatigue, hematuria, and discomfort in both the upper abdominal areas. He presented with fever but no respiratory symptoms at the time of the visit, and SARS-CoV-2 PCR test was positive. On admission, he had clear consciousness, and his vital signs were temperature of 36.9°C, blood pressure of 228/152 mm Hg, pulse rate of 81/minutes, respiratory rate of 16/minutes, and SpO 2 of 98% on ambient air. Physical examination revealed dark red blood cell deposits throughout the oral cavity and petechial purpura on the extremities. No eyelid conjunctival pallor was observed. Blood  tests revealed severe thrombocytopenia and AKI with platelets of 1000/μL, creatinine of 5.17 mg/dL, and blood urea nitrogen of 79.5 mg/dL (Table 1). In addition to mild anemia, elevated lactate dehydrogenase (LDH) and decreased haptoglobin levels were observed. CD4-positive lymphocyte was 590/μL, and HIV-RNA viral load was undetectable. Computed tomography revealed no obvious pneumonia or intra-abdominal hemorrhage. None of the patient's family members had renal disease. The patient smoked 1 pack of cigarettes per day from age 20 years to the present, drank 350 ml/day of beer, and had not been vaccinated against SARS-CoV-2. The patient was considered to have TMA because of low platelet count, AKI, low haptoglobin, and high LDH level. Prothrombin time, activated partial thromboplastin time, fibrinogen level, and fibrin/fibrin degradation products were normal, and disseminated intravascular coagulation was excluded. PLASMIC score [19] was 5 points. Considering the possibility of TTP, steroid pulse therapy (methylprednisolone 1000 mg for 3 days) was initiated on the second day of the disease, followed by prednisolone 1 mg/kg/day (Fig. 1). PE and hemodialysis were initiated on the same day. Continuous intravenous nicardipine was initiated to markedly elevate the blood pressure. As he had no central nervous system symptoms, twenty units of platelets were transfused on the first and second days. As he did not show pneumonia or oxygen demand, the patient was judged to have mild COVID-19 based on the World Health Organization's severity classification, [20] and antiviral treatments for SARS-CoV-2 were not initiated.
On the 5th day, platelets increased to 51,000/μL after 2 plasma exchanges. ADAMTS13 activity was 73%, showing no decrease, and TTP was ruled out. Glucocorticoids were tapered and discontinued. Systolic blood pressure dropped below 180 mmHg, and nicardipine administration was terminated on the 6th day. However, on the day after termination, the systolic blood pressure rose again to 200 mm Hg. Blood tests showed a decrease in platelet count to 26,000/μL and an increase in LDH level. Twenty units of platelets were transfused over 2 days. Intravenous nicardipine was resumed to maintain systolic blood pressure below 140 mm Hg. Blood pressure was well-controlled with oral nifedipine (80 mg), doxazosin, and trichloromethiazide. On the ninth day, platelets increased to 138,000/μL. As the blood pressure stabilized at approximately 130 mm Hg, intravenous nicardipine was terminated. Renal function gradually improved, and on the 19th day, creatinine decreased from 5.6 mg/dL (first day) to 3.06 mg/dL, and urinary findings also improved; therefore, hemodialysis was terminated. ART was resumed with raltegravir, TAF, and FTC. His general condition stabilized and was discharged on the 28th day. The patient was under outpatient observation, and no similar episodes were observed for up to 8 months after discharge.

Discussion
Here, we report the case of a patient with a well-controlled HIV infection who was diagnosed with simultaneous COVID-19 and TMA based on the findings of AKI, thrombocytopenia, and hemolytic anemia. The multidisciplinary treatment for TMA includes glucocorticoids, PE, hemodialysis, and antihypertensive medications for extreme hypertension. The patient was discontinued from dialysis and his renal function recovered.

Author
The cases of COVID-19-related TTP had a female predominance (69.6%), with a mean age of 46.8 years. Three of the 23 patients had a history of TTP. All included patients (n = 18, 78.2%) had a reported ADAMTS13 activity of < 10%. None of the patients underwent renal biopsy. The majority (n = 19, 82.6%) of patients were diagnosed with TTP at the onset of COVID-19. Nineteen patients (82.6%) underwent plasma exchange, and all patients received glucocorticoids. Eleven patients (45.8%) received rituximab, 7 (29.2%) received caplacizumab, and 5 (20.8%) received intravenous immunoglobulin. Three patients (13.0%) underwent hemodialysis. Five patients (21.7%) died, with death more frequently in the TMA cases.
Our patient presented with thrombocytopenia, AKI, and hemolytic anemia (elevated LDH and low haptoglobin levels), suggesting TTP, aHUS, or TMA. TTP was ruled out because ADAMTS13 activity was normal. He had no history of medications that could induce TMA. Shiga toxin-producing Escherichia coli associated HUS was ruled out because no Shiga toxin was detected in the stool, and diarrhea symptoms were absent. aHUS may be caused by inherited pathogenic mutations in complement genes or autoantibodies directed against complement proteins. Although genetic testing and antibodies against complement factors are required to diagnose aHUS, these tests were not performed because the complement function results were normal in this case.
We discuss the possible causes of secondary TMA. Malignant hypertension is a well-known cause of TMA. In our patient,  hypertension was noted prior to admission, and his systolic blood pressure was approximately 150 mmHg. A history of hypertension, high mean arterial pressure, significant renal impairment, modest thrombocytopenia, and lack of severe ADAMTS13 deficiency (activity < 10%) at diagnosis are clues for diagnosing malignant hypertension-induced TMA. [74,75] Several patients have been reported to be in remission with blood pressure control alone without PE. [76][77][78] In this case, malignant hypertension-induced TMA was considered; however, severe thrombocytopenia was observed and atypical. Several previous reports on COVID-19-related TMA have described patients with a history of hypertension. [23,25,26,33,35] Therefore, concluding that hypertension alone induced TMA is difficult, and we concurrently administered PE and glucocorticoids. Conversely, the fact that the patient's condition improved with appropriate antihypertensive therapy suggests that extreme hypertension may have exacerbated the disease. TMA associated with HIV infection was less likely to be involved in this case because 10 years had passed since the onset of the HIV infection, and the patient had good compliance. The anti-HIV drugs were unlikely related to TMA because it required only a short time for symptoms to appear after changing the drugs, and the drugs were not reported to cause drug-induced TMA. The lack of improvement in renal impairment and requirement for several antihypertensive drugs prompted us to use raltegravir and TAF/FTC as anti-HIV drugs. Based on these findings, TMA secondary to COVID-19 was diagnosed. In this case, TMA was caused by the absence of COVID-19 symptoms, such as upper respiratory symptoms. Secondary TMA generally develops in parallel with the activity of the primary disease and may not occur in TMA secondary to COVID-19. PE, glucocorticoids, hemodialysis, and blood pressure control contributed to improvements in renal function and thrombocytopenia. PE has been previously reported to be effective. The importance of blood pressure control has been suggested because the disease is exacerbated when blood pressure control is inadequate. He developed AKI requiring hemodialysis but responded well to treatment. Dialysis was discontinued, and renal function returned to baseline.
COVID-19-related TMA should be considered as a differential diagnosis during the COVID-19 epidemic. Excessive inflammation and severe COVID-19 are not essential for TMA development. Early intervention with conventional TMA treatments, such as PE and corticosteroids, might be important in improving prognosis while differentiating between TTP and aHUS. Antihypertensive therapy may be helpful in the treatment of COVID-19-associated TMA.